Benzyl N-phenyl-2,2,2-trifluoroacetimidate: A new and stable reagent for O-benzylation

Article abstract of DOI:10.1246/cl.2007.992

A new O-benzylation reagent, benzyl N-phenyl-2,2,2-trifluoroacetimidate, has been developed. It even reacts with sterically hindered alcohols and base-sensitive hydroxy esters to afford the corresponding benzyl ethers catalyzed by TMSOTf in 1,4-dioxane. This reagent was more stable than benzyl 2,2,2-trichloroacetimidate, a known benzylation reagent. Copyright

Full text of DOI:10.1246/cl.2007.992

992
Chemistry Letters Vol.36, No.8 (2007)
Benzyl N-Phenyl-2,2,2-trifluoroacetimidate:
A New and Stable Reagent for O-Benzylation
Yasunori Okada, Mamiko Ohtsu, Masafumi Bando, and Hidetoshi Yamadaꢀ
School of Science and Technology, Kwansei Gakuin University, 2-1 Gakuen, Sanda 669-1337
(Received May 8, 2007; CL-070496; E-mail: hidetosh@kwansei.ac.jp)
A new O-benzylation reagent, benzyl N-phenyl-2,2,2-tri-
NPh
CF3
NaH, CH2Cl2
fluoroacetimidate, has been developed. It even reacts with steri-
cally hindered alcohols and base-sensitive hydroxy esters to
afford the corresponding benzyl ethers catalyzed by TMSOTf
in 1,4-dioxane. This reagent was more stable than benzyl
2,2,2-trichloroacetimidate, a known benzylation reagent.
+
BnOH
3
Cl
0 °C to rt
2 h, 98%
4
Scheme 2. Preparation of the new benzylation reagent 3.
3 (1.1 equiv.)
TMSOTf (0.1 equiv.)
OH
OBn
The benzyl group is one of the most indispensable protect-
ing groups for a hydroxy group in organic synthesis, because
its stability has been substantiated in numerous syntheses.1
Among a variety of benzylations,2 the Williamson ether synthe-
sis, the reaction between metal alkoxides and benzyl halides, has
been widely used in organic synthesis.3 However, the alkaline
reaction conditions limit the applicable substrates. Therefore,
new methods for benzylation under non-basic conditions have
been an important demand.
Benzyl trichloroacetimidate (1) is one of the reagents for
benzylation under non-basic conditions (Scheme 1).4 The reac-
tion between 1 and a hydroxy group was catalyzed by triflic acid
(TfOH) to afford benzyl ethers along with the release of trichlo-
roacetamide.4d,5 The trichloroacetimidate group was generally
developed as a leaving group for glycosylations.6 Recently, Yu
and Tao reported a modified glycosyl imidate 2 that has N-phen-
yl-2,2,2-trifluoroacetimidate as a leaving group.7 Thus, we ex-
pected that the N-phenyl-2,2,2-trifluoroacetimidate group could
be diverted to a leaving group in the benzylation. We herein
report a new reagent for benzylation, benzyl N-phenyl-2,2,2-tri-
fluoroacetimidate (3), which is stable at room temperature for
months and activated by acid-catalysts.
The new benzylation reagent 3 was prepared from benzyl
alcohol and N-phenyl-2,2,2-trifluoroacetimidoyl chloride (4)8
in the presence of NaH (Scheme 2).9 The use of neutral silica
gel for the purification of 3 was important for its reproducible
preparation. The compound 3 is a low viscosity liquid at
25 ꢁC, and soluble in a wide variety of solvents.
First, the optimal solvent was determined to be dimethoxy-
ethane (DME) and 1,4-dioxane. During the investigations, 2-
phenylethanol (5) and TMSOTf were the benzyl acceptor and
the catalyst, respectively (Scheme 3). The examined solvents
Ph
Ph
5 Å MS, Solvent, rt
5
6
Scheme 3. Investigation of the optimal solvent.
and resulting yields (in parentheses, %) of the corresponding
benzyl ether 6 were as follows: CH3CN (0), DMF (0), DMSO
(0), Et2O (24), THF (16), cyclopentylmethyl ether (trace),
CH2Cl2 (24), DME (95), 1,4-dioxane (94), and toluene (14).
Powdered 5 A molecular sieves (MS) were added as a dehydrat-
ing agent to avoid the hydrolysis of 3 that induces the formations
˚
˚
of benzyl alcohol and dibenzyl ether. The use of 4 A MS decreas-
ed the reaction rate.
Next, the use of several Brønsted and Lewis acids was inves-
tigated as the catalyst (Table 1). The reactions were examined in
DME and 1,4-dioxane. However, none of them afforded a better
yield than with TMSOTf. In most cases, the use of 1,4-dioxane
produced a better yield. In the investigations using Brønsted
acids (Entries 1–4), the use of TfOH in 1,4-dioxane was
effective. Among the Lewis acids, Sn(OTf)3, Sc(OTf)3, and
Yb(OTf)3 provided yields greater than 80% in 1,4-dioxane.
.
The use of BF3 Et2O was not effective in both of the solvents.
Thus, the use of TMSOTf in 1,4-dioxane at rt was fixed as the
standard condition for our further investigations.
The scope of the benzylation with 3 is as follows (Table 2).
Although a reaction with phenol did not proceed (Entry 12), the
reactions of the aliphatic secondary and tertiary alcohols pro-
ceeded smoothly (Entries 2–6). This method was also applicable
to hydroxy esters (Entries 7–11) which benzylation is difficult
under conventional basic conditions. No racemization occurred
during the benzylation of ethyl (S)-mandelate (14). Thus, the
non-basic O-benzylation with 3 would be expected to become
an effective method in organic synthesis.
ROH
cat. TfOH
The typical procedure for the benzylation is as follows: to a
stirred mixture of 3 (125 mg, 0.450 mmol), 5 (50.0 mg,
˚
0.409 mmol), and 5 A MS (50 mg) in 1,4-dioxane (4 mL) under
an N2 atmosphere, TMSOTf (9.1 mg, 0.041 mmol) was added.
The reaction mixture was stirred for 30 min at rt, then quenched
with Et3N (30 mg). The mixture was filtered through a cotton-
Celite pad to remove MS and evaporated. The resulting residue
was purified by preparative TLC (stationary phase: silica-gel,
eluant: 15/1 hexane/diethyl ether) to afford 6 (81.7 mg, 94%)
as colorless oil.
NH
CCl3
NH2
O CCl3
ROBn
BnO
1
NPh
CF3
NPh
CF3
O
(BnO)n
BnO
O
2
3
Scheme 1. Benzyl trichloroacetimidate (1), Yu’s glycosyl
donor (2), and the new benzylation reagent 3.
Copyright ꢀ 2007 The Chemical Society of Japan

Chemistry Letters Vol.36, No.8 (2007)
993
Table 1. Benzylation of 2-phenylethanol with various acid
catalysts
even for the benzylation of hindered alcohols and base-sensitive
hydroxy esters. The most remarkable feature of this reagent is
its stability. Two months storage of neat 3 in air at rt produced
no decomposition, and the 2-month-old 3 reacted as well as
the fresh one with 5 to afford 94% yield of 6; thus it is more
stable than 1.10 Preparation of the 4-methoxybenzyl analog of
3 according to Scheme 2 was unsuccessful in our hands.
3 (1.1 equiv.)
Acid (0.1 equiv.)
5
6
DME or 1,4-dioxane
5 Å MS, rt
Time
/h
Yield
/%
Entry
Acid
Solvent
We thank Professor Itaru Sato for the use of chiral HPLC
columns. This work was partly supported by the Grant-in-Aid
for Scientific Research from the Ministry of Education, Culture,
Sports, Science and Technology, Japan.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
HClO4
DME
1,4-dioxane
DME
1,4-dioxane
DME
1,4-dioxane
DME
1,4-dioxane
DME
1,4-dioxane
DME
1,4-dioxane
DME
1,4-dioxane
1
1
52
70
66
88
68
89
73
83
trace
83
27
trace
N.R.
N.R.
TfOH
0.25
0.25
0.5
0.5
0.5
1
1
1
2
1
Sn(OTf)2
Sc(OTf)3
Yb(OTf)3
Cu(OTf)2
References and Notes
1
M. Schelhaas, H. Waldmann, Angew. Chem., Int. Ed. Engl.
1996, 35, 2056.
2
a) W.-C. Yang, X.-A. Lu, S. S. Kulkarni, S.-C. Hung, Tetra-
hedron Lett. 2003, 44, 7837. b) Y. Kobashi, T. Minowa,
T. Mukaiyama, Chem. Lett. 2004, 33, 1362. c) H. Aoki, T.
Mukaiyama, Chem. Lett. 2005, 34, 1016. d) H. Aoki, T.
Mukaiyama, Bull. Chem. Soc. Jpn. 2006, 79, 1255. e) T.
W. Greene, P. G. M. Wuts, in Protective Groups in Organic
Synthesis, 4th ed., John Wiley and Sons, New York, 2007,
pp. 102–120, and references cited therein.
.
BF3 Et2O
—
—
3
4
M. B. Smith, J. March, in March’s Advanced Organic
Chemistry, Reaction, Mechanism, and Structure, 5th ed.,
John Wiley and Sons, New York, 2001, pp. 477–478.
a) T. Iversen, D. R. Bundle, J. Chem. Soc., Chem. Commun.
1981, 1240. b) H.-P. Wessel, T. Iversen, D. R. Bundle,
J. Chem. Soc., Perkin Trans. 1 1985, 2247. c) U. Widmer,
Synthesis 1987, 568. d) P. Eckenberg, U. Groth, T. Huhn,
N. Richter, C. Schmeck, Tetrahedron 1993, 49, 1619.
F. Cramer, N. Hennrich, Chem. Ber. 1961, 94, 976.
R. R. Schmidt, J. Michel, Angew. Chem., Int. Ed. Engl. 1980,
19, 731.
a) B. Yu, H. Tao, Tetrahedron Lett. 2001, 42, 2405. b) M.
Adinolfi, G. Barone, A. Iadonisi, M. Schiattarella, Tetrahe-
dron Lett. 2002, 43, 5573.
K. Tamura, H. Mizukami. K. Maeda, H. Watanabe, K.
Uneyama, J. Org. Chem. 1993, 58, 32.
Table 2. Scope of the benzylation with 3
3, TMSOTf
ROH
ROBn
1,4-dioxane, 5 Å MS
Equiv.
of 3
Equiv.
of cat.
Time
/h
Yield
/%
Entry
ROH
Temp.
1
2
3
4
5
6
7
8
9
7
8
9
1.5
2.0
5.0
1.1
3.0
2.0
1.1
2.0
1.1
1.5
1.5
1.1
0.3
0.1
0.2
0.1
0.5
0.3
0.1
0.1
0.1
0.1
0.1
0.1
rt
rt
rt
rt
1
2
94
92
93
99
95
81
91
91
95
83
73
N.D.
5
6
12
1.5
13
12
0.5
1.5
0.5
0.5
1
10a
11
12
13
14
15
16
17
18
rt
7
60 ꢁC
rt
60 ꢁC
rt
8
9
10
11
12
60 ꢁC
60 ꢁC
rt
The procedure for the preparation of 3 is as follows: To the
stirred suspension of BnOH (2.34 g, 21.7 mmol) and 4
(5.00 g, 24.1 mmol) in CH2Cl2 (120 mL), NaH (964 mg,
24.1 mmol) was added at 0 ꢁC. The mixture was stirred for
2 h at rt. After an addition of H2O (0.1 mL), the mixture
was evaporated and diluted with hexane (50 mL). The result-
ing mixture was filtered through a cotton-Celite pad, and the
filtrate was evaporated. The resulting residue was purified by
neutral silica-gel column chromatography (100 g of SiO2:
Silica Gel 60 N, pH 6.5–7.5, 40–50 mm, Kanto Chemical
Co., Inc., hexane/Et2O 50/1) to afford 3 (5.93 g, 98%) as
—
a) (+)-Dihydrocholesterol.
OH
Ph
OH
Ph
OH
HO
H
7
8
9
10
OH
O
O
OH
Ph
OH
OH
EtO
EtO
14
2
2
1
11
12
13
pale yellow oil at rt, mp 19–20 ꢁC; H NMR (400 MHz in
CDCl3): ꢀ 7.48–7.38 (m, 5H), 7.33 (dddd, J ¼ 7:3, 6.7,
2.3, 2.3 Hz, 2H), 7.13 (ddd, J ¼ 7:6, 7.3, 1.2 Hz, 2H), 6.85
(br d, J ¼ 8:0 Hz, 2H), 5.34 (s, 2H); 13C NMR (100 MHz
in CDCl3): ꢀ 145.3 (q, JC{C{F ¼ 34:3 Hz), 144.5, 135.2,
O
O
OH
OH
OH Cl
O
O
Ph
O
O
OH
2
2
15
16
17
18
128.9, 128.8, 128.7, 128.4, 124.1, 119.7, 116.4 (q, JC{F
285:1 Hz), 69.8.
¼
In conclusion, 3 was developed as an O-benzylation reagent
under non-basic conditions. The best result was obtained when
TMSOTf catalyzed it in 1,4-dioxane. The reaction was effective
10 The trichloroacetimidate 1 can be stored at 5 ꢁC as solutions
in hexane for periods of up to 2 months: see Ref. 4b.
Published on the web (Advance View) June 30, 2007; doi:10.1246/cl.2007.992